5-Lipoxygenase is the first dedicated enzyme in the pathway leading to the biosynthesis of leukotrienes. This important enzyme has a rather restricted distribution, being found predominantly in leukocytes and mast cells of most mammals. Normally 5-lipoxygenase is present in the cell in an inactive form; however, when leukocytes respond to external stimuli, intracellular 5-lipoxygenase can be rapidly activated. This enzyme catalyzes the addition of molecular oxygen to fatty acids with cis,cis-1,4-pentadiene structures, converting them to 1-hydroperoxy-trans,cis-2,4-pentadienes. Arachidonie acid, the 5-lipoxygenase substrate which leads to leukotriene products, is found in very low concentrations in mammalian cells and must first be hydrolyzed from membrane phospholipids through the actions of phospholipases in response to extracellular stimuli. The initial product of 5-lipoxygenase action on arachidonate is 5-hydroperoxyeicosatetraenoic acid (5-HPETE) which can be reduced to hydroxyeicosatetraenoic acid (5-HETE) or converted to leukotriene A.sub.4 (LTA.sub.4). This reactive leukotriene intermediate is enzymatically hydrated to leukotriene B.sub.4 (LTB.sub.4) or conjugated to the tripeptide, glutathione, to produce leukotriene C.sub.4 (LTC.sub.4). LTA.sub.4 can also be hydrolyzed nonenzymatically to form two isomers of LTB.sub.4. Successive proteolyfic cleavage steps convert LTC.sub.4 to leukotrienes D.sub.4 and E.sub.4 (LTD.sub.4 and LTF.sub.4). Other products resulting from further oxygenation steps have also been described in the literature. Products of the 5-lipoxygenase cascade are extremely potent substances which produce a wide variety of biological effects, often in the nanomolar to picomolar concentration range.
The remarkable potencies and diversity of actions of products of the 5-lipoxygenase pathway have led to the suggestion that they play important roles in a variety of diseases. Alterations in leukotriene metabolism have been demonstrated in a number of disease states including asthma, allergic rhinitis, rheumatoid arthritis, gout, psoriasis, adult respiratory distress syndrome, inflammatory bowel disease, endotoxin shock syndrome, atherosclerosis, ischemia induced myocardial injury, and central nervous system pathology resulting from the formation of leukotrienes following stroke or subarachnoid hemorrhage.
The enzyme 5-lipoxyganase catalyzes the first step leading to the biosynthesis of all the leukotrienes and therefore inhibition of this enzyme provides an approach to limit the effects of all the products of this pathway. Compounds which inhibit 5-lipoxygenase are thus useful in the treatment of disease states such as those listed above in which the leukotrienes play an important role.
U.S. Pat. No. 3,859,305 to Posselt, et at. discloses certain indole aminoketones which are useful as cardiovascular agents.
U.S. Pat. No. 3,931,229 to Zinnes, et at. discloses and claims certain 3-thiomethyl-(2-[2-(dialkylamino)ethyt]indoles having utility as central nervous system depressants and anti-aggression agents.
U.S. Pat. No. 4,021,448 to Bell discloses and claims certain 2-substituted-indole-1-(lower alkane)carboxarnides having utility for decreasing gastric secretions and as anti-ulcer agents.
U.S. Pat. No. 4,119,638 to Ray discloses and claims certain thioesters of 1-(4-chlorobenzoyl)-5-methoxy-2-methylindole-3-acetic acid useful as antiinflammatory agents.
U.S. Pat. No. 4,464,379 to Betzing, et at. discloses and claims certain 1-(4-chlorobenzoyl)-2-methyl-5-methoxyindole-3-acetic acid derivatives having antithrombic, antiarteriosclerotic, and antiphlogisfic activity.
European Patent Application 87 31103 1.6 (Publication No. 0 275 667) to Gillard, et at. discloses and claims certain 3-(hetero-substituted)-N-benzylindoles as leukotriene biosynthesis inhibitors.
S. Raucher, et at., in "Indole Alkaloid Synthesis via Claissen Rearrangement," J. Am. Chem. Soc., 103(9):2419-2412 (1981), disclose certain 1H-indole-2-acetic acid derivatives.
Kobayashi, et al., in "Indole Derivatives XlI. Reaction of Indole-2-carboxylic Acid Derivatives with Carbon Disulfide," Yakugaku Zasshi, 91(11): 1164-1173 (1971) (in Japanese; Chemical Abstracts English-language abstract: CA76: 46033k (1972)), disclose the synthesis of certain 1-methyl-2-carboxarnido-3-(dithioester)-indoles.